Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers
Open accessAbstract
Significance: Mammalian SWI/SNF (mSWI/SNF) alterations are highly prevalent, now estimated to occur in 20% of cancers. The inactivating nature of mSWI/SNF mutations presents a challenge for devising strategies to target these epigenetic lesions. By performing a comprehensive pooled shRNA screen of the epigenome using a unique deep coverage design shRNA (DECODER) library across a large cancer cell line panel, we identified that BRG1/SMARCA4 mutant cancer cells are highly sensitive to BRM/SMARCA2 depletion. Our study provides important mechanistic insight into the BRM/BRG1 synthetic lethal relationship, shows this finding translates in vivo, and highlights BRM as a promising therapeutic target for the treatment BRG1 -mutant cancers.
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SMARCA2 is essential for growth of tumor cells that harbor loss-of-function mutations in SMARCA4.
“Whereas SMARCA2 is essential for the growth of tumor cells that harbor loss of function mutations in SMARCA4 [166].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [166]
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- Authors
- Hoffman, G. R., Rahal, R., Buxton, F., Xiang, K., McAllister, G., Frias, E., Bagdasarian, L., Huber, J., Lindeman, A., Chen, D., Romero, R., Ramadan, N., Phadke, T., Haas, K., Jaskelioff, M., Wilson, B. G., Meyer, M. J., Saenz-Vash, V., Zhai, H., Myer, V. E., Porter, J. A., Keen, N., McLaughlin, M. E., Mickanin, C., Roberts, C. W. M., Stegmeier, F., & Jagani, Z.
- Affiliations
- Departments of aDevelopmental and Molecular Pathways and
- Oncology, Novartis Institutes for BioMedical Research, Cambridge, MA 02139;
- Oncology Translational Medicine, Novartis Pharma, Cambridge, MA 02139; and
- Dana-Farber Cancer Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-11
- Volume
- 111
- Issue
- 8
- Pages
- 3128-3133
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3939885
- OpenAlex
- W2031541159
- Cited by
- 421
- References
- 37
- Citations by year
- 2026: 36 · 2025: 33 · 2024: 47 · 2023: 32 · 2022: 28 · 2021: 28 · 2020: 38 · 2019: 35 · 2018: 25 · 2017: 27 · 2016: 37 · 2015: 34 · 2014: 20
- FWCI
- 16.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- synthetic lethality, SWI/SNF complex, H3K9me3, cell cycle arrest, senescence, lung adenocarcinoma, shRNA screen
- MeSH terms
- DNA Helicases, Histones, Humans, Neoplasms, Nuclear Proteins, Transcription Factors, Blotting, Western, Gene Library, Cellular Senescence, RNA, Small Interfering, Epigenesis, Genetic, Cell Line, Tumor, Multiprotein Complexes, Immunoprecipitation, Gene Knockdown Techniques, Cell Cycle Checkpoints
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